Acquired Genetic Changes In Cancer Flashcards
What are the three categories of acquired genetic change in cancer?
- Formation of a chimaeric protein
- Gain/amplification (of gene/gene product)
- Deletion/loss of function of a gene
Provide some details on the formation of a chimaeric protein in the context of oncology cytogenetics
- balanced rearrangement (e.g. Translocations, inversions, insertions)
- Fusion of two genes results in production of chimaeric protein
- Usually involves a TF: change to control mechanism means it is continuously switched on
- Cascade of other genes then switched on
What are some examples in oncology involving formation of chimaeric proteins?
- t(9;22) in CML (Philadelphia chr; BCR/ABL1)
- t(15;17) in APML (PML/RARA)
- Inv(16) in AML (CBFB/MYH11)
Increase of a gene or gene product in oncology can be subdivided into which two categories?
- Increase in copy number of an oncogene (arises through unbalanced abnormality)
- Increase in expression of an oncogene (arises through balanced abnormality)
Provide details on increase of a gene or gene product arising through increase in the copy number of an oncogene
Gain of copies of gene(s) by unbalanced cytogenetic abnormality, which can include:
- Dup of part of/whole chromosome
- Amp of smaller DNA segment including oncogene in form of double minutes/homogenous staining regions (=many fold increase in copy)
Give some examples of an increase of a gene or gene product arising through increase in copy number of an oncogene
- Trisomy8 in MDS/AML
- Neuroblastoma (amp results in increased copy number more than 4-fold relative to ploidy level)
What are double minutes in the context of oncology?
- Small, circular frags of extrachromosomal DNA observed in large number of tumours
- no centromere/telomere, replicate in nucleus during cell division
- Often contain amplified oncogenes or genes involved in drug resistance
Provide details on increase of a gene or gene product arising through increase in the expression of an oncogene
- Balanced rearrangement can place unaltered oncogene next to promoter region of another highly transcribed gene resulting in massive upregulation of the oncogene
What are the two subtypes of loss of a gene or gene product in the context of oncology cytogenetics?
- loss of tumour suppressor gene (common) - both copies usually compromised within tumour
- haploinsufficiency for dosage sensitive gene(s)
What are the different mechanisms behind loss of a gene or gene product in oncology cytogenetics?
- Loss of whole chr (unbalanced)
- Deletion of part of chr (unbalanced)
- mutation within a gene (balanced)
- loss of heterozygosity (balanced)
Provide some examples of loss of a gene or gene product in cancer cytogenetics
- RB1 (tumour suppressor gene) - patients with bilateral retinoblastoma usually have constitutional mutation in one copy, when other copy is mutated/lost retinoblastoma develops
- TP53 (TSG) located at 17p = guardian of the genome - patients with constitutional mutations of TP53 have Li Fraumeni syndrome with very high risk of developing cancer (P53 loss seen in many)
What are the 5 main methods of detecting genetic changes in oncology?
- Conventional cytogenetics
- FISH
- PCR
- Microarray
- NGS
What are the pros and cons of using cytogenetics for detecting genetic changes in oncology?
Pros
- gives undirected, whole genome screen for that cell
- detects balanced and unbalanced abnormalities
- WHO disease classes are linked to cytogenetics
Cons
- requires fresh tissue to provide dividing cells
- requires experienced analyst as can be complex and difficult to interpret
Give some examples of probe types used in oncology FISH
- Two colour colocalisation FISH
- Two colour dual fusion probes (e.g. BCR/ABL1)
- Two colour split apart probes (e.g. MLL)
What are the pros of using FISH for oncology testing?
- can be used on metaphase preps or non-dividing cells
- can be used on archive material e.g. PETs
- large numbers of cells can be scored
- detects balanced and unbalanced abnormalities
